Pharmacology of Postoperative Nausea and Vomiting

34 

Pharmacology of Postoperative Nausea and Vomiting ERIC S. ZABIROWICZ AND TONG J. GAN

CHAPTER OUTLINE Historical Perspective Mechanisms of Nausea and Vomiting Serotonin Receptor Antagonists Ondansetron Granisetron and Dolasetron Palonosetron Dopamine Receptor Antagonists Droperidol Haloperidol Metoclopramide Corticosteroids NK1 Receptor Antagonists Aprepitant Scopolamine H1-Receptor Antagonists Dimenhydrinate and Diphenhydramine Promethazine GABA Receptor Agonists Propofol Benzodiazepines Opioid Receptor Antagonists Naloxone Alvimopan Cannabinoids Risk-Based Prophylaxis Enhanced Recovery After Surgery Multimodal Therapy Emerging Developments Novel Antiemetic Drugs Postdischarge Nausea and Vomiting

Historical Perspective In the first half of the 20th century, one of the most feared complications of general anesthesia was postoperative vomiting (POV), primarily because aspiration of gastric contents into the lungs

could lead to death. Early prophylaxis sometimes consisted of advising patients to consume olive oil before general anesthesia to shield the intestinal wall from emetogenic gases. Prevention of POV was one of the primary motivations for developing local/ regional anesthesia blocks, first with cocaine and procaine, then with lidocaine. Postoperative nausea, on the other hand, was considered too minor a complication to measure—until the development in the 1950s and 1960s of anesthetic drugs that could be cleared more rapidly (e.g., halothane, barbiturates, and novel opioids), which meant that patients spent more of the immediate postoperative period awake.1 While the antiemetic effect of some drugs, such as anticholinergics, were first described more than a century ago, modern understanding of the specific receptor pathways and intracellular processes involved in postoperative nausea and vomiting (PONV) is relatively recent. It was not until the 1950s that interest in antiemetic drugs took off, with the identification of histamine and dopamine receptors in the nausea and vomiting pathway, and hence the clinical utility of H1- and D2-receptor antagonists like cyclizine, chlorpromazine, and promethazine. This surge in research on antiemetics was largely driven by advances in chemotherapy and a focus on chemotherapy-related outcomes. For example, neuro-oncologists first noticed the antiemetic effect of corticosteroids before the same observation was made for PONV in the 1990s.1 The development of 5-hydroxytryptamine type 3 (5-HT3)receptor antagonists marks the greatest advance in antiemetic drug research. Early 5-HT3-receptor antagonists were not more effective than other available antiemetics, but they were the first to be specifically designed by the pharmaceutical industry to target chemotherapy-induced nausea and vomiting (CINV) and PONV. This led to an increase in large, well-designed PONV studies, marketing of antiemetic agents, and a focus on PONV as a significant postoperative outcome.1 The first-generation 5-HT3receptor antagonists are associated with QTc prolongation, but the newest 5-HT3-receptor antagonists, palonosetron, appears to have improved efficacy, duration of action, and side effect profile compared with its predecessors. Neurokinin-1 (NK1)-receptor antagonists, such as aprepitant and rolapitant, are the newest class of antiemetic drugs, and they too benefit from a long duration of action and favorable side effect profile. As the current understanding of the nausea and vomiting pathway, pharmacokinetics and pharmacodynamics, and genetics continues to improve, antiemetic drugs are likely to become safer and easier to tailor to individual patients. 671



CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting 671.e1

Abstract

Keywords

Postoperative nausea and vomiting (PONV) are common problems following surgery. This chapter is designed to educate the readers on the spectrum of antiemetic therapy available, and to which populations the modalities may prove most useful. The pharmacology of both traditional and novel drugs is discussed as well as synergies gained from multi-modal combination drug therapy. The use of routine antiemetic prophylaxis is essential for a successful enhanced recovery pathway.

Multimodal drug therapy Risk-based prophylaxis Antiemetic prophylaxis vs. rescue therapy Enhanced Recovery after Surgery

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Mechanisms of Nausea and Vomiting Despite thousands of studies, new insights into target receptor function, and the successful development of novel antiemetic agents, the actual mechanisms of nausea and vomiting remain unclear. Most antiemetic drugs act on one of several putative neurotransmitter pathways. 5-HT3- receptor antagonists are the most commonly used antiemetic class of drugs (Table 34.1). Other classes include dopamine (D2), histamine (H1), NK1, gamma-aminobutyric acid (GABA) A , opioid, and muscarinic cholinergic receptor antagonists. The receptors on which antiemetics act certainly play a role in nausea and vomiting. However, given that only 20% to 30% of patients respond to any one agent, nausea and vomiting cannot be solely attributed to activity of one—or several—of these receptor classes. It is also likely that individual variability plays a larger role than previously acknowledged. Although it is essential to understand and investigate the drug-receptor relationship, the therapeutic potential of targeting specific receptor classes is limited.

Nausea and vomiting can be triggered by a variety of stimuli, including toxins, anxiety, adverse drug reactions, pregnancy, radiation, chemotherapy, and motion. These stimuli are integrated by the vomiting center in the nucleus tractus solitarius (NTS), located primarily in the medulla as well as in the lower pons. The vomiting center receives input from the adjacent chemoreceptor trigger zone (CTZ), the GI tract, the vestibular system, and the cerebral cortex (Fig. 34.1). The CTZ is located at the caudal end of the fourth ventricle in the area postrema, a highly vascularized structure that lacks a true blood-brain barrier. Therefore chemosensitive receptors in the CTZ can be directly stimulated by toxins, metabolites, and drugs that circulate in the blood and cerebrospinal fluid. The CTZ communicates with the vomiting center primarily via D2 receptors as well as 5-HT3 receptors. Enterochromaffin cells in the GI tract release serotonin, which stimulates vagal afferents that terminate in the CTZ and communicate information regarding intestinal luminal compounds and gastric tone. The vestibular system, located in the bony labyrinth of the temporal lobe, detects changes in Higher Central Nervous System Centers

5-HT 5-HT3, receptor Amygdala

• Fig. 34.1

Vagus nerve

Schematic of pathways involved in postoperative nausea and vomiting. 5-HT, 5-hydroxytryptamine; 5-HT3, 5-hydroxytryptamine type 3 receptor; AP, area postrema; NTS, nucleus tractus solitarius.  

Dorsal vagal complex

MEDULLA

AP and NTS Central pattern generator

Chemotherapy Enterochromaffin cells

SMALL INTESTINE

Vagal afferents

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

equilibrium, which can cause motion sickness. Histamine (H1 receptor) and acetylcholine (muscarinic acetylcholine receptors) are the neurotransmitters that communicate between the vestibular system and the vomiting center. Anticipatory or anxiety-induced nausea and vomiting probably originates in the cerebral cortex. The cortex has direct input to the vomiting center via several types of neuroreceptors.

Serotonin Receptor Antagonists Serotonin (5-HT3) receptors are ligand-gated sodium ion (Na+) and potassium ion (K+) channels found throughout the central and peripheral nervous systems, notably in the CTZ and afferent fibers of the vagus nerve in both the gut and central nervous system (CNS; see Fig. 34.1). Serotonin activation of the CTZ and vagal afferents can both trigger the vomiting reflex. Serotonin plays an important role in anesthesia-, chemotherapy-, and radiation-induced nausea and vomiting. Serotonin receptor antagonists can be used as antiemetic treatment because they inhibit both central and peripheral stimulation of 5-HT3 receptors, and they are effective, nonsedative, and generally well tolerated. Thus 5-HT3-receptor antagonists are currently the most commonly used antiemetic agents for PONV, CINV, and rescue treatment.

Ondansetron Ondansetron was the first 5-HT3-receptor antagonist approved by the U.S. Food and Drug Administration (FDA), and at the time of its development, was the safest and most effective treatment for early CINV.2 Its reputation for superior CINV prophylaxis carried over to PONV, but a factorial trial in more than 5000 patients showed that 4 mg ondansetron was only as effective as 4 mg dexamethasone and 1.25 mg droperidol for PONV.3 Contrary to the common clinical impression that ondansetron is less effective against nausea than against vomiting, the relative risk reduction (RRR, risk ratio) of ondansetron is the same for nausea and for vomiting.4 However, ondansetron’s plasma half-life is only about 4 hours, which is probably why several studies found it to be more efficacious when administered toward the end rather than at the beginning of anesthesia.5 Like other 5-HT3-receptor antagonists, ondansetron’s side effects are generally mild to moderate and include constipation and headache, the latter of which is increased by about 3%.6 First-generation 5-HT3-receptor antagonists like ondansetron have also been associated with QTc prolongation, which potentially increases the risk of cardiac arrhythmia and cardiac arrest.7 The QTc prolongation associated with ondansetron use is similar to that caused by droperidol.8 Even though 5-HT3-receptor antagonists are among the most effective antiemetic treatments for CINV, 20% to 30% of patients do not respond to 5-HT3-receptor antagonism in the early phase of CINV.9 Furthermore, 50% to 60% of high-risk patients do not respond to these drugs in the late phase of CINV.10,11 Several studies have shown that responsiveness to ondansetron appears to be modulated by variations in cytochrome P450 enzyme 2D6 (CYP 2D6) activity and the ABCB1 gene. The ability to predict patient responsiveness to 5-HT3-receptor antagonists based on genetic testing for known polymorphisms could prove to be an important breakthrough in individualizing antiemetic therapy. Ondansetron is partially metabolized by hepatic CYP 2D6. There are numerous CYP 2D6 polymorphisms, each associated with one of four metabolic phenotypes: poor (no functional alleles), intermediate (less activity than one functional allele), extensive

673

90 80 Incidence of POV (%)



70 60 50 40 30 20 10 0

Poor

Intermediate Extensive

Ultrarapid

Metabolizer status

• Fig. 34.2

  Patients with a genotype associated with ultrarapid metabolism (i.e., three functional copies of CYP 2D6) are at increased risk for postoperative vomiting (POV) after prophylaxis with ondansetron in the first 24 postoperative hours. (Adapted from Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005;102:543–549.)

(two functional alleles, and the most common phenotype), and ultrarapid (three functional alleles). Ultrarapid metabolizers can degrade ondansetron more quickly and are therefore less likely to benefit from prophylaxis with the drug. In fact, several studies have shown that patients with three CYP 2D6 alleles, especially those with three functional alleles, are significantly more likely to experience PONV after prophylaxis with ondansetron than patients with fewer alleles (Fig. 34.2).9,12 Ultrarapid metabolism by CYP 2D6 is believed to be partially responsible for prophylactic ondansetron failures in individuals with an ultrarapid metabolic genotype, whereas other enzymes that metabolize ondansetron—namely, CYP 3A4, CYP 2E1, and CYP 1A2—are thought to play a larger role in drug clearance in individuals with poor, intermediate, and extensive metabolism genotypes.12 Ondansetron pharmacokinetics also appear to be modulated by polymorphisms of the gene that codes for the drug efflux transporter adenosine triphosphate–binding cassette subfamily B member 1 (ABCB1). The ABCB1 pump transports at least three 5-HT3-receptor antagonists, including ondansetron, across the blood-brain barrier, thereby limiting accumulation of these drugs in the CNS.13 Polymorphisms of ABCB1 that reduce its activity increase the concentration of 5-HT3-receptor antagonists in the brain, which enhances efficacy. Indeed, cancer patients with a 3435C>T genetic polymorphism were less likely to experience chemotherapy-induced vomiting (CIV) in the first 24 hours after prophylaxis with ondansetron. 13 Similarly, 3435C>T and/or 2677G>T/A polymorphisms are associated with a lower incidence of PONV in surgery patients, but only within the first 2 postoperative hours.14

Granisetron and Dolasetron Other first-generation 5-HT3-receptor antagonists include granisetron and dolasetron. Both drugs have a plasma half-life about

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TABLE 34.1  Properties of Individual Antiemetic Drugs

Empirical Formula

Administration

Daily Dosage (mg) PONV CINV

1,2,3,9-tetrahydro-9-methyl-3-[(2methyl-1H-imidazol-1-yl)methyl]-4Hcarbazol-4-one, monohydrochloride, dihydrate

C18H19N3O

IV

4

endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3carboxamide hydrochloride (2α,6α,8α,9αβ)-octahydro-3-oxo-2,6methano-2H-quinolizin-8-yl-lHindole-3-carboxylate monomethanesulfonate, monohydrate 1αH,5αH-Tropan-3α-yl indole-3carboxylate (3aS)-2-[(S)-1-Azabicyclo [2.2.2] oct-3-yl]-2,3,3α,4,5,6-hexahydro-1oxo-1H benz[de]isoquinoline hydrochloride

C18H24N4O

IM Oral Sup IV Oral TD IV Oral

4 16 16 1 1 3.1 12.5 100

IV Oral IV Oral

2 5 0.075 0.075

5 5 0.25 0.5

15.1 3.46 5.6

25

3.2

Chemical Name

Cmax (ng/mL)

5-HT3 Receptor Antagonists Ondansetron (Zofran)

Granisetron (Kytril) Dolasetron (Anzemet) Tropisetron (Navoban) Palonosetron (Aloxi)

C19H20N2O3

C17H20N2O2 C19H24N2O

32 (0.15 mg/kg × 3) 8 8×2 16 10 µg/kg 2 3.1

64

100

D2 Receptor Antagonists Droperidol Haloperidol (Haldol) Metoclopramide (Reglan)

1-[1-[3-(p-Fluorobenzoyl) propyl]1,2,3,6-tetrahydro-4-pyridyl]-2benzimidazolinone 4-[4-(p-chloro-phenyl)-4hydroxypiperidino]-4′— fluorobutyrophenone 4-amino-5-chloro-N-[2-(diethylamino) ethyl]-2-methoxybenzamide monohydrochloride monohydrate

C22H22FN3O2

IV IM

0.625–1.25 × 6–8 0.625–1.25 × 6–8

C21H23ClFNO2

IV IM Oral IV

1–2

IM Oral

25–50

9-fluoro-11β, 17,21-trihydroxy-16αmethylpregna-1,4-diene-3,20-dione

C22H29FO5

IV IM SC Oral

4

C14H22ClN3O2

25–50

100 (1–2 mg/kg) × 8–12

Corticosteroids Dexamethasone

4×4 4×4 4×4

NK1 Receptor Antagonists Aprepitant (Emend)

5-([(2R,3S)-2-((R)-1-[3,5bis(trifluoromethyl)phenyl]ethoxy)-3(4-fluorophenyl)morpholino] methyl)-1H-1,2,4-triazol-3(2H)-one

C23H21F7N4O3

Oral

40

α-(hydroxymethyl) benzeneacetic acid 9-methyl-3-oxa-9-azatricyclo [3.3.1.02,4] non-7-yl ester

C17H21NO4

TD

0.5

Anticholinergics Transdermal scopolamine (Transderm Scop)

125 D1/80 D2-3

0.7 (40 mg); 1.6 (125 mg); 1.4 (80 mg)

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting



AUC (ng•hr/mL)

Tmax (hr)

0.4

Bioavailability (%)

Vd (L/kg)

56

Protein Bound (%)

Metabolism

70–76

CYP 3A4, CYP 1A2, CYP 2D6

Plasma Half-Life (hr)

Adverse Effects

Other

Constipation, headache, QTc prolongation

No sedation

675

4

0.7 1.5–2.2

527

20.7 32.9 35.8

48 0.6 1

60

3

65

CYP 3A

75

5.8

69–77

CYP 2D6, CYP 3A, flavin monooxygenase

8

71

CYP 3A4, CYP 1A2, CYP 2D6 CYP 2D6, CYP 3A, CYP 1A2

6–8

60–80 2.6 97

8.3

62

3–14 HPB black box warning (Canada)

40

No QTc prolongation

EPS, QTc prolongation 69

1.5

>90

2–3

50–60

18

92

12–36

80

3.5

30

5–6

17.8

0.2–0.3 3–6 1–2

80–90

70

CYP 3A4

36–54a

FDA black box warning

Cumulative CINV doses associated with significant EPS

10 mg PONV dose insufficient EPS <1% at 25–50 mg

Hyperglycemia

Most dose response studies suggest that 4 mg is sufficient No sedation

7.8 (40 mg); 3 (40 mg); 4 19.6 (80–125 mg) (125 mg); 21.2 (80 mg) <24

60–65 (80–125 mg)

10–50

>95

CYP 3A4, CYP 1A2, CYP 2C19

9–13

72a

Continued

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TABLE 34.1  Properties of Individual Antiemetic Drugs—cont’d

Empirical Formula

Administration

[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4dimethyl-1-piperidinyl]methyl]-1-oxo3-phenylpropyl]amino]acetic acid dihydrate

C25H32N2O4

Oral

Diazepam (Diastat, Valium)

7-chloro-1,3-dihydro-1-methyl-5phenyl-2H-1,4-benzodiazepin-2-one

C16H13ClN2O

Lorazepam (Ativan)

7-chloro-5-(o-chlorophenyl)-1,3dihydro-3-hydroxy-2H-1,4benzodiazepin-2-one

C15H10Cl2N2O2

Midazolam

8-chloro-6-(2-fluorophenyl)-1-methyl4H-imidazo [1,5-a][1,4] benzodiazepine hydrochloride

C18H13ClFN3

IV IM Oral Sup IV IM Oral TD IV IM Oral

Chemical Name

Daily Dosage (mg) PONV CINV

Cmax (ng/mL)

Opioid Receptor Antagonists Alvimopan (Entereg)

GABA Agonists

1.5 mg/m2

20

2.5 × 2 90

H1 Receptor Antagonists Dimenhydrinate (Dramamine) Promethazine (Phenergan)

2- (diphenylmethoxy)-N,N -dimethylethylamine hydrochloride 10-[2- (Dimethylamino)propyl] phenothiazine monohydrochloride

C17H21NO

C17H20N2S

IV IM Oral Sup IV IM Oral Sup

50–100 × 4–6 50–100 × 4–6 50–100 × 4–6

80–110

12.5–25 × 4–6 12.5–25 × 4–6 25 × 2 25 × 2

AUC, Area under the curve; CINV, chemotherapy-induced nausea and vomiting; Cmax, maximum plasma concentration; CYP, cytochrome 450; D, day; D2, dopamine 2; EPS, extrapyramidal symptoms; 5-HT3, 5-hydroxytryptamine type 3 (serotonin); GABA, gamma-aminobutyric acid-A; H1, histamine 1; HPB, Health Protection Branch (Canada); IM, intramuscular; IV, intravenous; NK1, neurokinin-1; PONV, postoperative nausea and vomiting; QTc, heart-rate corrected QT interval; SC, subcutaneous; Sup, suppository; TD, transdermal;; Tmax, time to maximum plasma concentration; Vd, volume of distribution. a Indicates duration of action.

twice as long as ondansetron. In general, 5-HT3-receptor antagonists are considered equally effective at equipotent doses. Compared with 4 mg ondansetron, 12.5 mg dolasetron and 1 mg granisetron appear to be the minimal effective dose for the prevention of PONV.15 Both drugs are associated with side effects similar to those of ondansetron, including QTc prolongation. CYP 2D6, the enzyme responsible for partial metabolism of ondansetron, is the primary enzyme for dolasetron metabolism. 12 In contrast, granisetron is primarily metabolized by CYP 3A4 and not at all by CYP 2D6.12 Therefore the efficacy of dolasetron might be modulated by the CYP 2D6 polymorphisms mentioned earlier, whereas ABCB1 polymorphisms might play a larger role in enhancing the efficacy of granisetron.

Palonosetron Palonosetron is the newest and most effective 5-HT 3-receptor antagonist for preventing acute and delayed emesis associated with chemotherapy and for reducing nausea severity (Fig. 34.3).16,17 Palonosetron is characterized by 2500-fold greater affinity than serotonin and 100-fold greater affinity than other 5-HT3-receptor antagonists.18 Palonosetron also has a long half-life of 40 hours.

However, palonosetron’s high binding affinity and long half-life cannot explain its superiority to other 5-HT3-receptor antagonists. High binding affinity does not account for palonosetron’s superiority against higher doses of dolasetron or ondansetron (i.e., higher doses of less potent drugs do not overcome the potency difference). Similarly, a long half-life cannot account for palonosetron’s superiority against more frequent redosing of ondansetron.17 Instead, recent research suggests that palonosetron’s high efficacy can be attributed to the manner in which it binds to 5-HT3 receptors.17 Whereas other 5-HT3-receptor antagonists bind only to the agonist binding site, palonosetron also binds at an allosteric site that increases receptor affinity for the receptor antagonist at the agonist binding site.16 Given that granisetron and ondansetron induce little to no receptor internalization, this allosteric binding might also be responsible for palonosetron’s relatively high rate (50%–60%) of receptor internalization and low receptor exocytosis. Internalized receptor-antagonist complexes are less likely to be dissociated, and, in turn, bound receptors are less likely to be exocytosed and subsequently reactivated by agonists at the cell surface. The low receptor density at the cell surface owing to palonosetron results in prolonged inhibition of receptor function— that is, protection against delayed emesis. Indeed, studies have

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting



AUC (ng•hr/mL)

Tmax (hr)

Bioavailability (%)

2

6

0.5–2 1–1.5

90–100

2

90

0.8–1.0

Protein Bound (%)

Metabolism

80–90

Intestinal flora

95–98

CYP 2C19, CYP 3A4

Plasma Half-Life (hr)

1–3.1

Adverse Effects

Other

Sedation

Limited evidence

Necrosis that may require amputation

FDA black box warning

20

85

>90

0.5

Vd (L/kg)

9–16

97

CYP 3A4

2–6

61

78

CYP 2D6

2–9

25

93

2–3 16–19

CH3

O

N

HO

NH2 N H Serotonin

NN CH3

Tropisetron

Granisetron

N N CH3

N

N

O

O HO

Ondansetron

• Fig. 34.3

N N H

O N H

CH3

O

N N

O N H

O

H Palonosetron

Dolasetron

  Palonosetron and other 5-hydroxytryptamine type 3 receptor antagonists. The structure of the serotonin is shown on the left.

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Gastrointestinal and Endocrine Systems

100 75

No 5-HT3 Receptor Antagonist

50 25 0

Ca2+ internal release

SE C T I O N V

Ca2+ internal release

678

125

75 50 25 0

–8.5 –7.5 –6.5 –5.5 –4.5 –3.5 –2.5

Ondansetron

100

–8.5 –7.5 –6.5 –5.5 –4.5 –3.5 –2.5

SP concentration (M, log scale) SP

125

SP + 5-HT

Granisetron

100 75 50 25 0

C

B

Ca2+ internal release

Ca2+ internal release

A

SP concentration SP SP + 5-HT SP + 5-HT + Ondansetron 100

Palonosetron

75 50 25 0

–8.5 –7.5 –6.5 –5.5 –4.5 –3.5 –2.5

–8.5 –7.5 –6.5 –5.5 –4.5 –3.5 –2.5

SP concentration

SP concentration

SP SP + 5-HT SP + 5-HT + Granisetron

D

SP SP + 5-HT SP + 5-HT + Palonosetron

• Fig. 34.4

  The effect of 5-hydroxytryptamine type 3 receptor antagonists on serotonin enhancement of substance P (SP)-induced intracellular calcium ion (Ca2+) release. NG108-15 neuroblastoma cells were incubated with SP and subsequently exposed to serotonin. A, Serotonin (5-HT) enhancement of the SP response. Ondansetron (B), granisetron (C), and palonosetron (D) were preincubated with NG108-15 cells for 2 hours, then removed, after which serotonin was added and the SP response was measured. Unlike ondansetron and granisetron, palonosetron can partially reduce serotonin enhancement of SP activity. (From Rojas C, Li Y, Zhang J, et al. The antiemetic 5-HT3 receptor antagonist palonosetron inhibits substance P-mediated responses in vitro and in vivo. J Pharmacol Exp Ther. 2010;335:362–368.)

shown that prophylaxis with palonosetron decreases CIV in a significant proportion of patients in the 5 days following chemotherapy treatment.19 Another mechanism that contributes to palonosetron’s high efficacy is its inhibition of cross talk between 5-HT3 and NK1 receptor signaling pathways.20 Palonosetron and the NK1 agonist substance P (SP) cannot bind to each other’s respective target receptors. However, serotonin and SP enhance each other’s potency, and 5-HT3-receptor antagonists and NK1-receptor antagonists block activation of vagal afferents by the other agonist.20 Palonosetron is associated with a sixfold reduction in serotonin enhancement of SP potency in vitro (Fig. 34.4). Granisetron and ondansetron, on the other hand, had no effect on SP potency in vitro. In an in vivo study in rat nodose ganglia, palonosetron reduced cisplatin-induced SP activation for hours after cisplatin administration.20 Palonosetron thus appears to have a prolonged downstream effect on SP function in vitro and in vivo that might be due to palonosetron’s ability to cause 5-HT3 receptor internalization and reduce receptor density at the cell surface. Studies have shown that 0.25 mg and 0.075 mg palonosetron are effective doses for preventing CINV and PONV, respectively, and with a half-life of 40 hours, palonosetron provides therapeutic effect for a 72-hour period.19,21 Unlike other 5-HT3-receptor

antagonists, palonosetron is not associated with QTc prolongation. Palonosetron’s long half-life makes it a potentially important treatment for postdischarge nausea and vomiting (PDNV), although its relative efficacy in this setting has yet to be demonstrated.

Dopamine Receptor Antagonists Droperidol Low-dose (0.625–1.25 mg intravenously [IV]) droperidol is an effective antiemetic for treatment of PONV and opioid-induced nausea and vomiting (OINV), with similar efficacy against nausea (RR [relative risk] = 0.65) and vomiting (RR = 0.65).3,22 Droperidol has a short half-life of 3 hours and, if used for the prevention of PONV, should be administered toward the end of anesthesia. At low doses, droperidol is an α-adrenergic receptor blocker that causes increased sedation (RR = 1.32).23 Therefore for PONV prophylaxis, droperidol should be administered at the minimum effective dose of 0.625 mg IV to reduce the risk of adverse effects. For OINV prophylaxis, although 50 µg of droperidol is the most effective dose to add to a morphine or piritramide patient-controlled analgesia (PCA) infusion pump, 25 µg of droperidol is the safer, recommended dose.24



CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

In 2001, reports of arrhythmia and death associated with use of droperidol led the FDA to attach a black box warning to the drug’s label, after which droperidol use decreased 10-fold in the United States. According to the new label, droperidol is contraindicated in patients with known or suspected QT prolongation. Therefore absence of QT prolongation must be confirmed by electrocardiogram before droperidol administration, and electrocardiogram monitoring must be continued for 2 to 3 hours after drug administration. Many hospitals have removed droperidol from their formularies or placed restrictions on its use, in addition to drug shortages, so that droperidol usage is less than 2% of cases in the United States, even though more than 90% of anesthesiologists believe that the FDA black box warning is unwarranted.25 Those who argue against the black box warning question the clinical relevance of droperidol-induced QT prolongation, particularly because QT prolongation is associated with general anesthesia itself, as well as other drugs commonly administered during surgery (e.g., antibiotics). QTc prolongation after placebo, 0.625 mg droperidol, and 1.25 mg droperidol were 12, 15, and 22 msec, respectively.26 Similarly, 0.75 mg droperidol and 4 mg ondansetron were associated with 17- and 20-msec QT prolongation, respectively.8 It is possible, however, that these studies were inadequately powered to include patients with a rare but clinically significant predisposition to QT prolongation.8,26 Of note, there are polymorphisms in the ether-à-go-go related gene (hERG) receptor that occur in about 0.5% to 2% of the population, and it is possible that these are the patients who are at high risk when exposed to droperidol. Thus it is not possible to exclude the possibility that adding droperidol to other QT-prolonging interventions, including general anesthesia, can trigger QT prolongations that lead to cardiac arrhythmia.27

Haloperidol As a result of the black box warning for droperidol, there is a renewed interest in haloperidol, an older butyrophenone. Haloperidol is an effective treatment for psychiatric disorders at high doses and is an effective antiemetic at low doses. Haloperidol has a longer plasma half-life of 10 to 20 hours after intravenous administration. Like other D2-receptor antagonists, haloperidol is associated with extrapyramidal effects, including acute dystonia, pseudoparkinsonism, and akathisia.28 Haloperidol is metabolized in the liver, where 23% of haloperidol is reduced by a carbonyl reductase into a functional metabolite with high binding affinity to σ-opioid and D2 and D3 receptors.28 However, there is significant interindividual variation in haloperidol pharmacokinetics.28 Plasma concentrations of haloperidol correlate with dosage, drug efficacy, and incidence of adverse effects.28 Although CYP 3A4 is the primary enzyme responsible for haloperidol metabolism, with CYP 2D6 appearing to play only a minor role, several studies have shown that certain CYP 2D6 genotypes are associated with poor metabolism and are correlated with higher haloperidol plasma concentrations and lower drug clearance than genotypes associated with extensive metabolism (Fig. 34.5A and B). Specifically, individuals with 0, 1, 2, and more than 2 active CYP 2D6 alleles are considered poor, intermediate, extensive (most common), and ultrafast metabolizers, respectively. Thus poor metabolizers are at higher risk for adverse effects than are intermediate and extensive metabolizers.28 Reports of QT prolongation, torsades de pointes, and sudden death associated with use of haloperidol similar to those associated with droperidol led the FDA to issue an FDA alert for haloperidol

679

in 2007. It has not received a black box label because these severe adverse effects occurred in patients who had received off-label intravenous administration of haloperidol at doses greater than 35 mg/day, whereas only intramuscular administration has been approved by the FDA.

Metoclopramide Metoclopramide, a procainamide derivative and a benzamide prokinetic agent, is the most commonly used D2-receptor antagonist for antiemetic prophylaxis, primarily for PONV and chemotherapy associated with low emetogenic risk. It is assumed that both the central D2-receptor antagonist activity at the CTZ and vomiting center and peripheral activity in the GI tract contribute to the antiemetic effect. Metoclopramide acts on peripheral D2, muscarinic, and 5-HT4 receptors to induce prokinetic activity. Opioids can cause delayed gastric emptying, but metoclopramide enhances gastric motility and increases intestinal peristalsis, which reduces reflux of stomach contents and the urge to vomit. Because of its short half-life of 5 to 6 hours, metoclopramide is likely to have greatest efficacy if administered at the end of surgery. Metoclopramide was first prescribed for CINV in high doses (e.g., 200 mg every 4–6 hours), which cause extrapyramidal symptoms in more than 10% of patients.29 To reduce the incidence of adverse effects, metoclopramide is available in vials of just 10 mg. However, extensive studies and a meta-analysis have demonstrated that 10 mg metoclopramide has no clinically relevant antiemetic effect.30 In fact, a large and well-designed dose-response study in more than 3000 patients demonstrated that doses of 25 and 50 mg metoclopramide are effective in reducing PONV by about 37% (RR = 0.63, a similar efficacy as other commonly used antiemetics), whereas the rate for extrapyramidal symptoms was less than 1% (see Fig. 34.5C).31 Like haloperidol, metoclopramide is metabolized primarily by CYP 2D6. Although several studies have shown CYP 2D6 polymorphisms that result in reduced CYP 2D6 activity are associated with a higher incidence of metoclopramide adverse effects, no studies have investigated yet whether CYP 2D6 polymorphisms influence the antiemetic efficacy of the drug. Given that nearly 25% of metoclopramide is excreted unchanged, however, the effect of CYP 2D6 polymorphisms might be relatively small, at least in patients with normal renal function. Like other D2-receptor antagonists, metoclopramide is associated with severe cardiac adverse effects.32 High doses are associated with a high incidence of extrapyramidal symptoms, but lower doses (25–50 mg) are associated with a less than 1% incidence of dyskinetic and/or extrapyramidal symptoms.31 It is important to note that the FDA issued a black box warning for metoclopramide, given the high risk of developing tardive dyskinesia if metoclopramide use extends beyond 12 weeks. However, this concern likely does not apply to a short-term course of metoclopramide in the perioperative setting. Other D2-receptor antagonists such as alizapride, perphenazine, and prochlorperazine might be as effective as other commonly used antiemetics, but they are rarely used, and their side effect profiles are unclear compared with that of other antiemetics.22

Corticosteroids Dexamethasone is a synthetic glucocorticoid with antiinflammatory and immunosuppressant properties. With 20 to 30 times the binding affinity for glucocorticoid receptors of endogenous cortisol,

Gastrointestinal and Endocrine Systems

SE C T I O N V

Reduced haloperidol/dose [10–3/L]

680

n=3

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n = 99

n=4

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• Fig. 34.5  Dependence of reduced haloperidol serum trough levels (A) and extrapyramidal symptoms (EPS) (B) on CYP 2D6 genotype after haloperidol doses of 2 to 24 mg. On the x-axis, 0 = no active alleles; 1 = 1 active allele; 2 = 2 active alleles; and 3 = 1 active and 1 or 2 duplication alleles. Black lines show medians, blue boxes show interquartile ranges, and error bars show the ranges of measured data. C, Cumulative incidence of postoperative nausea and vomiting (PONV) in treatment groups receiving placebo or 10, 25, and 50 mg metoclopramide. (A and B, From Brockmoller J, Kirchheiner J, Schmider J, et  al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther. 2002;72:438–552; C, From Wallenborn J, Gelbrich G, Bulst D, et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ. 2006;333:324.)

2.00

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dexamethasone is a potent treatment for PONV and CINV. Even though dexamethasone is one of the most commonly used antiemetics, its mechanism of action remains unclear. Studies in animal models suggest that dexamethasone acts on the glucocorticoid receptor–rich bilateral NTS (i.e., the vomiting center), but not the area postrema.33 Although 8 mg is the most commonly used dose for prevention of PONV, dose-response studies suggest that 5 mg is the minimum effective dose for PONV prophylaxis (Fig. 34.6).34 Furthermore, a large factorial trial in more than 5000 patients found that 4 mg dexamethasone has similar efficacy to 4 mg ondansetron or 1.25 mg droperidol.35 Thus ambulatory surgery guidelines recommend 4 to 5 mg dexamethasone.36 Dexamethasone is more effective when given at the beginning rather at the end of surgery, which suggests that there is a delay in onset of action by about 2 hours.37 Furthermore, a single intraoperative dose of dexamethasone has not been associated with adverse effects.36 However, like other intravenous drugs containing phosphate esters, dexamethasone has been associated with perineal burning and itching when injected in awake patients.38 In addition, doses of 12 to 20 mg can be given for CINV.39 Dexamethasone is an effective and well-tolerated component of antiemetic combination therapy.35 Adding aprepitant to the typical treatment regimen for CINV—a 5-HT3-receptor antagonist (ondansetron) and a corticosteroid (dexamethasone)—further reduces the incidence of CINV. The doses of aprepitant recommended for CINV (125 mg on day 1, 80 mg on days 2 and 3) moderately inhibits CYP 3A4, the enzyme responsible for dexamethasone metabolism. In fact, aprepitant’s inhibition of CYP 3A4 activity approximately doubles the plasma concentration of dexamethasone (Fig. 34.7). Given that dexamethasone has high (80%) oral bioavailability, and that aprepitant also increases the peak plasma concentration and half-life of dexamethasone, aprepitant’s inhibition of CYP 3A4 activity probably plays a larger role in systemic rather than first-pass clearance of dexamethasone.40 Therefore doses of dexamethasone that are coadministered with aprepitant should be reduced by half to maintain dexamethasone plasma concentrations that are similar to regimens without aprepitant. The pharmacokinetics of ondansetron, which is partially metabolized by CYP 3A4, are not affected by aprepitant.40

NK1 Receptor Antagonists NK1 receptors are G-protein–coupled receptors found in both the central and peripheral nervous systems. NK1 receptors are

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting



Striatal NK1 receptor occupancy (%)

0.6

Incidence (%)

0.5 0.4 0.3 0.2 0.1 Nausea

Vomiting

Placebo 5 mg* dexamethasone

>4 vomiting Use of rescue episodes antiemetics

1.25 mg dexamethasone 10 mg* dexamethasone

2.5 mg dexamethasone

• Fig. 34.6

  Incidence of nausea, vomiting, severe vomiting, and need for rescue antiemetics 0 to 24 hours after dexamethasone prophylaxis in a dose-ranging study. *P < 0.05 compared to placebo. (From Wang JJ, Ho ST, Lee SC, et al. The use of dexamethasone for preventing postoperative nausea and vomiting in females undergoing thyroidectomy: a dose-ranging study. Anesth Analg. 2000;91:1404–1407.)

350 Dexamethasone concentration (ng/mL)

100 90 80 70 60 50 40 30 20 10 0 0

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681

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Aprepitant plasma concentration (ng/mL)

• Fig. 34.8

  High correlation between aprepitant plasma concentration and NK1 receptor occupancy (0.97 [P < 0.001; 95% confidence interval = 0.94-1.00]). (From Bergstrom M, Hargreaves RJ, Burns HD, et al. Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry. 2004;55:1007–1012.)

reduce emesis associated with a range of stimuli, including cisplatin, cyclophosphamide, irradiation, ipecacuanha, copper sulfate, opioids, and motion.41 NK1 receptor antagonists competitively inhibit SP binding to central NK1 receptors, effectively preventing neurotransmission within the central pattern generator for vomiting.42 Because cisplatin increases plasma levels of SP, NK1 receptor antagonists are particularly important for the prevention and treatment of CINV.43

250

Aprepitant

200 150 100 50 0

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6

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Time (hr) 20 mg oral dexamethasone + 32 mg ondansetron IV 125 mg oral aprepitant + 20 mg oral dexamethasone + 32 mg ondansetron IV 125 mg oral aprepitant + 12 mg oral dexamethasone + 32 mg ondansetron IV

• Fig. 34.7

  Mean plasma concentration profiles of dexamethasone when combined with other antiemetics. Aprepitant markedly increased the plasma concentration of dexamethasone. IV, Intravenous. (From McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the NK1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74:17–24.)

found in the GI tract and in high concentrations in regions responsible for regulating the vomiting reflex, including the brainstem nuclei, the NTS, and the area postrema. SP, a member of the tachykinin family of neuropeptides, is the dominant ligand of NK1 receptors. In animal models, SP activation of NK1 receptors in the area postrema induces retching, and NK1 receptor antagonists

Currently aprepitant is the only FDA-approved NK1 receptor antagonist. Aprepitant has greater efficacy for preventing vomiting than any other single intervention, with RR reductions of more than 50%.41,44 Furthermore, aprepitant has greater efficacy against both acute and delayed POV and CIV.43,45,46 Aprepitant is available as an oral capsule that is easy to coadminister with other surgical premedication for PONV prophylaxis. Whereas aprepitant is highly effective on its own, it reaches its optimal efficacy against early emesis when combined with other antiemetics, such as 5-HT3receptor antagonists and/or dexamethasone.43,45,46 Its efficacy against nausea, however, appears to be comparable to other treatment options.41 Like 5-HT3-receptor antagonists, aprepitant is nonsedative; it has a long half-life of 9 to 13 hours. Furthermore, aprepitant is not associated with QTc prolongation.41 Aprepitant is primarily metabolized by CYP 3A4; CYP 1A2 and CYP 2C19 also contribute to its metabolism. Positron emission tomography studies have shown that aprepitant can penetrate the blood-brain barrier to bind to NK1 receptors in the area postrema.47 The FDA-approved dose of aprepitant for PONV prophylaxis is 40 mg, which is associated with only 75% receptor occupancy (Fig. 34.8). Doses of 100 mg or more, such as the FDA-approved 125 mg for CINV prophylaxis, are sufficient to achieve greater than 90% NK1 receptor occupancy. Patients with cancer typically receive 125 mg aprepitant the day of chemotherapy, followed by 2 days of 80 mg aprepitant.48 Aprepitant doses as high as 375 mg are associated with the same level of receptor occupancy as 125 mg and thus have no clinical advantage.

Gastrointestinal and Endocrine Systems

Scopolamine Scopolamine is a competitive antagonist of acetylcholine at muscarinic receptors, and the most effective single agent for preventing motion sickness.49 Scopolamine is available in oral, parenteral, and transdermal formulations. The 0.3- to 0.6-mg oral and 0.2-mg parenteral doses are associated with a short duration of action of 5 to 6 hours and some adverse effects, most commonly dry mouth, drowsiness, and blurred vision.50 Redosing with oral or parenteral doses can result in variable drug plasma concentrations, which if too high are associated with severe autonomic and CNS effects and if too low are associated with inadequate antiemetic efficacy. A transdermal formulation of scopolamine was developed to overcome the limited half-life and clinical efficacy of the oral and parenteral formulations. A transdermal delivery system is also an advantage when oral doses are intolerable. Transdermal scopolamine (TDS) is available in a thin (0.2-mm) patch made up of four layers: an outer membrane, a drug reservoir mixed with mineral oil and polyisobutylene, a rate-limiting microporous membrane, and an adhesive layer closest to the skin. In vitro studies using human cadavers show wide variation in skin permeability between both application sites and individuals. Therefore the patch is recommended for use at the postauricular site, a highly permeable area, and the rate-limiting microporous membrane has been designed to deliver scopolamine at a slower rate than that achieved in the least porous postauricular skin sample tested.49 In addition, the adhesive layer contains a 140-µg priming dose of scopolamine to overcome the skin as the primary compartment before a more constant scopolamine delivery leads to steady-state plasma concentrations. The drug reservoir contains 1.5 mg scopolamine that is released at a constant rate of about 5 µg/hr for 3 days. The controlled drug delivery decreases the incidence of adverse side effects compared with oral and parenteral formulations. 51,52 This delivery rate maintains therapeutic plasma concentrations, estimated to be greater than 50 pg/mL. Plasma concentrations greater than 50 pg/mL and antiemetic efficacy are both observed 6 hours after patch application (Fig. 34.9A).53,54 Drug efficacy peaks at plasma concentrations greater than 100 pg/mL, observed 8 to 12 hours after application. Therefore TDS should be administered ideally 4 to 6 hours before an antiemetic effect is required. However, supplementing TDS with 0.3 to 0.6 mg oral scopolamine results in therapeutic plasma concentrations after only 1 hour (see Fig. 34.9B and C).55

500 Total quantity of scopolamine permeated (µg/cm2)

The neurotransmitter acetylcholine acts on cholinergic receptors in the CTZ, vestibular system, and cerebellum. According to the current model of motion sickness, an orientation disparity comparator in the cerebellum compares expected sensory input from memory with actual sensory input, and any significant discrepancy between the two triggers symptoms of motion sickness. Acetylcholine might be involved in integrating sensory stimuli in the vestibular nuclei, as well as transmitting information regarding expected sensory input to the cerebellum. Therefore anticholinergic agents like scopolamine might facilitate habituation to motion by preventing acetylcholine from relaying signals to the comparator and instead allowing a new sensory pattern to develop that reflects the actual environment.49 Acetylcholine released from the gut wall also appears to increase gut motility and secretion. Anticholinergic agents thus play an important role in the prevention of motion sickness and PONV.

400 300 200 100 0

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TDS + 0.6 mg oral scopolamine

TDS + 0.3 mg oral scopolamine

TDS

  A, In vitro permeation of scopolamine at 30°C from various patch locations. B, Transdermal scopolamine (TDS) effects on plasma concentrations. Plasma concentrations of scopolamine persist up to 72 hours after TDS application (n = 15). C, Percentage of subjects with plasma scopolamine concentration greater than 50 pg/mL, 0 to 22 hours after treatment in three experimental groups. *P < 0.05 (Fisher’s exact test) when TDS + 0.6 mg and TDS + 0.3 mg are compared with TDS only group. (From Nachum Z, Shupak A, Gordon CR. Transdermal scopolamine for prevention of motion sickness: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2006;45:543–566.)

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting



TDS is an effective antiemetic intervention, associated with a risk reduction of 0.56 and 0.54 for PON and POV, respectively, if applied the night before surgery, and with a risk reduction of 0.61 and 0.74 for PON and POV, respectively, if applied the day of surgery.56 Interestingly, despite wide variation between individual plasma concentrations, correlation of plasma concentrations 8 hours after TDS application in the same individual on different occasions is still 0.52 (P < 0.05).57 TDS is generally well tolerated; adverse effects are similar to those associated with oral and parenteral scopolamine. The most common adverse effects are dry mouth, allergic contact dermatitis, and drowsiness. The drowsiness appears to be associated with PONV more than motion sickness.49 Scopolamine is not recommended for pediatric patients and should be used with caution in older patients because of the sedative effects and the risk of delirium.

H1-Receptor Antagonists H1-receptor antagonists can be used for management of motion sickness, PONV, and OINV. Agents like diphenhydramine, promethazine, and cyclizine are reversible competitive H1-receptor antagonists with moderate anticholinergic (antimuscarinic) and weak antidopaminergic activity. Although the mechanism of their antiemetic efficacy is not fully understood, H1-receptor antagonists likely act on receptors in the vestibular system and vomiting center.23 Side effects include drowsiness, dry mouth, blurred vision, urinary retention, and extrapyramidal symptoms.22,58 Although H1-receptor antagonists are generally well tolerated, cost-effective, and have been used in clinical practice for several decades, they have not been as well studied as other more recently developed antiemetics.59 Dose-response relationships, side effect profiles, and the benefit of repeat dosing remain unclear.58,60 Their efficacy against motion

sickness might give H1-receptor antagonists an important role in antiemetic prophylaxis for ambulatory patients.61

Dimenhydrinate and Diphenhydramine Dimenhydrinate is a theoclate salt composed of diphenhydramine, an ethanolamine derivative, and 8-chlorotheophylline, a chlorinated theophylline derivative, in a 1 : 1 ratio. Dimenhydrinate must be metabolized into its active ingredient diphenhydramine to attain antiemetic efficacy. Therefore dimenhydrinate has a slower onset of action and is administered as a 60-mg dose to match the potency of 30 mg diphenhydramine.59 Diphenhydramine itself undergoes N-demethylation to its principal metabolite monodesmethyldiphenhydramine (DMDP) in the liver.62 Oral diphenhydramine bioavailability ranges from 43% to 72%, probably owing to first-pass metabolism, with peak plasma concentrations of approximately 64 ng/mL after approximately 2.5 hours. 62,63 Plasma concentration of diphenhydramine covaries with that of DMDP (Fig. 34.10A). The observed plasma half-life of oral dimenhydrinate is 3 to 9.3 hours, and the elimination half-lives after intravenous and oral administration are 8.4 and 9.2 hours, respectively, for diphenhydramine and 9.3 and 7.3 hours, respectively, for DMDP (see Fig. 34.10B).64 The observed metabolite area under the curve (AUC) after oral administration (218 hr.ng/mL) is significantly larger than after intravenous administration (145 hr-ng/mL).64 Sedative and performance-impairing side effects are typically associated with diphenhydramine doses greater than or equal to 50 mg and differ from placebo only within the first 3 hours.62,65 Although there is a positive correlation between plasma concentration and sedative effects, there is also wide variation among individuals in the severity and persistence of these effects.65

300

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• Fig. 34.10  A, Plasma concentrations of diphenhydramine and its metabolite desmethyl diphenhydramine following intravenous and oral administration of diphenhydramine. B, Relation of clearance of intravenous diphenhydramine to total area under the plasma concentration-time curve (AUC) for the metabolite desmethyl diphenhydramine, as determined by linear regression analysis. Appearance of the metabolite thus mirrors the disappearance of diphenhydramine. (From Blyden GT, Greenblatt DJ, Scavone JM, et al. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol. 1986;26:529–533.)

9

Gastrointestinal and Endocrine Systems

A systematic review incorporating 18 clinical trials and 3045 patients demonstrated that diphenhydramine is associated with decreased POV and PONV, although its impact on PON was not significant.58 In addition, 50 mg IV dimenhydrinate is similarly effective as 4 mg IV ondansetron for the prevention of PONV in patients undergoing elective laparoscopic cholecystectomy.66 For management of motion sickness, 100 mg oral dimenhydrinate is superior to TDS, whereas 50 mg is similarly effective as TDS.49 For OINV management, diphenhydramine can be safely and effectively coadministered with morphine via a PCA pump, especially given the similar pharmacokinetic profiles of the two drugs. Administering 30 mg diphenhydramine at induction, followed by a 4.8 : 1 diphenhydramine-morphine solution via a PCA pump, reduced emesis without morphine-sparing or sedative effects.59 The initial intraoperative dose serves to establish a therapeutic plasma concentration before the infusion, thereby minimizing the risk of sedative side effects associated with larger diphenhydramine doses during the postoperative period.

Promethazine Promethazine is a phenothiazine derivative and a potent antihistamine with moderate antimuscarinic activity. Although more than 80% is absorbed, promethazine undergoes extensive first-pass hepatic glucuronidation and sulfoxidation, resulting in low absolute bioavailability of approximately 25%.67 Peak plasma concentrations of promethazine (2.4–18.0 ng/mL) are observed between 1.5 and 3 hours after administration (Fig. 34.11A). Like other drugs that undergo extensive hepatic first-pass metabolism, plasma concentrations of its metabolite, promethazine sulfoxide (PMZSO), peak earlier and higher following oral administration compared with intravenous administration (see Fig. 34.11B).67 Overall, however, PMZSO plasma AUCs are not significantly different following oral or intravenous administration. Time to effect after intravenous and intramuscular injection is 5 and 20 minutes, respectively.68 With a plasma half-life after intravenous and intramuscular injection of 9 to 16 hours and 6 to 13 hours, respectively, promethazine’s duration of effect is typically 4 to 6 hours, up to 12 hours.68 Promethazine is also effective for rescue treatment of established PONV and has been combined with 5-HT3-receptor antagonists and TDS to reduce both the frequency and severity of PONV.69–72 For PONV management, 12.5 to 25 mg is administered toward the end of surgery and every 4 hours, as needed, with doses of coadministered analgesics and/or barbiturates reduced accordingly.68 Studies investigating a 6.25-mg promethazine dose to reduce the incidence of sedative side effects have produced conflicting results on antiemetic efficacy.71 Because H1 receptors are involved in the development of inflammatory pain and hyperalgesia, administering antihistamines like promethazine can also reduce pain levels in addition to the incidence of emesis. In one study, preoperative administration of 0.1 mg/kg IV promethazine reduced postoperative morphine consumption by approximately 30% in the first 24 postoperative hours.73 Promethazine received a black box warning from the FDA in 2004 indicating that the drug should not be used in children younger than 2 years of age because of potential fatal respiratory depression. The warning label also recommends that promethazine should be administered with caution and at the lowest effective dose in children 2 years of age and older. The promethazine hydrochloride injection also received a black box warning from the FDA in 2009 indicating that severe tissue injuries, including gangrene, can rarely be associated with intravenous administration

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• Fig. 34.11

  Blood concentration-time profiles of promethazine (A) and promethazine sulfoxide (B) in a human volunteer following administration of 12.5 mg intravenous (IV, purple) or 25 mg oral (blue) promethazine. (From Taylor G, Houston JB, Shaffer J, et al. Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man. Br J Clin Pharmacol. 1983;15:287–293.)

of promethazine. In anesthesia practice it is important to inject promethazine only through a well-established and secure IV line or infuse the drug diluted in saline solution.

GABA Receptor Agonists Propofol Propofol has several mechanisms of action, including potentiation of GABAA receptors. Administration of propofol-based total intravenous anesthesia (TIVA) instead of volatile anesthetics can reduce the incidence of PONV by about 20%.35 That propofol



CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

has antiemetic effects is supported by the finding that repeat doses of 20 mg propofol via a patient-controlled delivery device in the postanesthesia care unit (PACU) significantly reduced PONV.74 However, this effect could not be reproduced in a similar study, and another study found that both propofol and midazolam had antiemetic properties only under clinical sedation.75,76 Therefore it is likely that the reduced incidence of PONV after TIVA with propofol compared with general anesthesia with inhaled gas is at least in part a result of not administering volatile anesthetics rather than the potential antiemetic effects of propofol. Some patients experience anticipatory nausea and vomiting before chemotherapy begins or earlier in the treatment regimen than expected. As a learned response to chemotherapy, anticipatory nausea and vomiting can affect up to 25% of patients by the fourth treatment cycle.77,78 However, much about its pathogenesis and management remains unclear.

Benzodiazepines Benzodiazepines are currently the most commonly used anxiolytics. These agents act as positive modulators of GABAA receptors. Increased GABAA receptor activity results in varying levels of CNS depression, including sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic effects. In addition to decreased anxiety, the mechanism of action of benzodiazepines is believed to involve GABAA receptor-mediated reduction of dopamine and 5-HT3 receptor activity in the CTZ.79 Another specific pathway that has been suggested is that benzodiazepines decrease adenosine reuptake, thereby leading to decreased synthesis, release, and postsynaptic activity of dopamine in the CTZ.80,81 GABAA-receptor activation is also associated with reduced opioid analgesia.82 Opioids are believed to produce an analgesic effect by inhibiting GABA-receptor pain modulation in the periaqueductal gray matter and the rostral ventral medulla. In one study, 0.75 mg IV flumazenil, a benzodiazepine antagonist, enhanced postoperative morphine analgesia in patients who received intravenous diazepam preoperatively compared with patients who did not receive flumazenil.82 Therefore opioid analgesia can be improved by using benzodiazepines of short duration of action and/or by coadministering flumazenil with morphine in the immediate postoperative period. Diazepam is typically administered as a 5- to 10-mg dose 2 hours before surgery. The agent appears to be effective against both nausea (RR = 0.50, 95% confidence interval [CI] 0.25–0.99) and vomiting (RR = 0.85, 95% CI 0.58–1.24).22 Because of a long half-life of more than 24 hours, other benzodiazepines with shorter durations of action, such as lorazepam and midazolam, can be used instead. Lorazepam is the preferred agent for anticipatory nausea and vomiting. It can also be used for the prophylaxis and treatment of PONV and CINV.83 Like diazepam, lorazepam appears to have a greater effect on nausea (RR = 0.55, 95% CI 0.33–0.93) than vomiting (RR = 0.61, 95% CI 0.33–1.13) compared with placebo.22 For PONV prophylaxis, patients receive 0.05 mg/kg (up to 4 mg maximum) 1 to 2 hours before surgery. For anticipatory nausea and vomiting, guidelines recommend 0.5 to 2 mg lorazepam on the night before and morning of surgery, and for CINV management, 0.5 to 2 mg every 4 to 6 hours on days 1 to 4 posttreatment.84 Lorazepam might be insufficient as an antiemetic on its own, but it can be safely combined with other antiemetic agents to manage CINV.85 A randomized controlled trial found lorazepam effective in managing anticipatory, acute, and delayed CINV, especially

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when coadministered with 2 mg/kg metoclopramide IV.86 Mild sedation (lethargy but arousable without any disorientation) and amnesia (no memory of chemotherapy treatment) were more common in patients treated with lorazepam. Lorazepam is readily absorbed into the bloodstream with an absolute bioavailability of 90%. Peak plasma concentrations of 20 ng/mL after a 2-mg dose are reached approximately 2 hours after administration. The plasma half-life of lorazepam is approximately 12 hours and 18 hours for its primary metabolite, lorazepam glucuronide. Intravenous midazolam is the most commonly used premedication in ambulatory surgery for induction of general anesthesia and preoperative sedation owing to its rapid onset of action, relatively short half-life, low cost, and low incidence of side effects.87 For PONV prophylaxis, a 2-mg dose of midazolam can be given before or after induction or postoperatively as a continuous infusion. Ahn and colleagues examined previous randomized controlled trials of midazolam and PONV via a database search. The investigation revealed a reduction in PONV (RR 0.45, number needed to treat 3) with similar findings for PON and POV in isolation.88 Midazolam is rapidly metabolized to 1′-hydroxymidazolam by both hepatic and intestinal CYP 3A4. Therefore drugs like aprepitant that inhibit CYP 3A4 activity could lead to prolonged sedation owing to increased exposure to midazolam. In a study in which healthy volunteers received a 2-mg dose of oral midazolam during the week preceding the study, a second dose on day 1, and a third on day 5, participants were randomly assigned to receive an aprepitant dosing regimen similar to CINV (125 mg on day 1 and 80 mg on days 2–5) or PONV prophylaxis (40 mg on day 1 and 25 mg on days 2–5).89 CINV doses of aprepitant led to a 2.3-fold increase in midazolam plasma AUC on day 1 and a 3.3-fold increase on day 5 (Fig. 34.12A, upper panel), as well as increased maximum observed plasma concentrations and half-life of midazolam. The latter can be explained by inhibition of both first-pass metabolism and systemic clearance of midazolam by aprepitant. PONV doses of aprepitant had no significant effect on oral midazolam metabolism (see Fig. 34.12A, lower panel). Because aprepitant cannot inhibit first-pass metabolism of CYP 3A4 substrates when they are given intravenously, it is not surprising that both CINV and PONV doses of aprepitant have no significant effect on intravenous midazolam metabolism (see Fig. 34.12B).90–92

Opioid Receptor Antagonists Although the FDA has not specifically approved the use of 5-HT3and D2-receptor antagonists for OINV, these agents significantly reduce the incidence of nausea and vomiting after opioid administration.93–97 Antiemetic agents that specifically target opioid receptors might also have efficacy against OINV, which has the advantage of simultaneously targeting multiple other opioid-induced adverse effects, such as postoperative ileus.98

Naloxone Other techniques to reduce PONV can come from novel uses of preexisting medications. One such technique is using a low-dose naloxone infusion to reduce the side effects of opioid administration. In one study the authors randomly assigned 60 patients receiving morphine PCA to a continuous infusion of naloxone 0.25 µg/kg per hour, 1 µg/kg per hours, or placebo. They found a reduced rate of adverse side effects, including nausea and vomiting, in both naloxone groups compared with the placebo group. Interestingly,

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  Interaction between midazolam and aprepitant. A, Plasma concentration-time profiles of 2 mg oral midazolam before the study, on day 1, and on day 5 when coadministered with 125 mg aprepitant on day 1 and 80 mg on days 2 to 5 in 8 healthy male subjects (upper panel). Plasma concentrationtime profiles of 2 mg oral midazolam before the study, on day 1, and on day 5 when coadministered with 40 mg aprepitant day 1 and 25 mg days 2 to 5 (lower panel). B, Plasma concentrations of midazolam when administered intravenously, alone, and with 125 mg oral aprepitant in 12 healthy subjects. C, Incidence of opioid-induced nausea and vomiting after prophylaxis with 6 and 12 mg alvimopan. CINV, Chemotherapy-induced nausea and vomiting; PONV, postoperative nausea and vomiting. (A, From Majumdar AK, McCrea JB, Panebianco DL, et al. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther. 2003;74:150–156; B, From Majumdar AK, Yan KX, Selverian DV, et al. Effect of aprepitant on the pharmacokinetics of intravenous midazolam. J Clin Pharmacol. 2007;47:744–750; C, From Adolor Corporation. Advisory Panel briefing document. Entereg (alvimopan) Capsules for postoperative ileus. 2007. Available at: http://www.fda.gov/ohrms/dockets/ ac/08/briefing/2008-4336b1-02-Adolor.pdf.)

there appeared to be an opioid-sparing effect in the low-dose naloxone group as this cohort used less morphine in the study period compared with placebo.99

Alvimopan Alvimopan, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, is approved by the FDA to reverse postoperative ileus after colectomy. Although opioids do have some peripherally mediated analgesic effects, opioid analgesia primarily involves central µ, κ, and δ receptors in the rostral anterior cingulate cortex, the brainstem, and the dorsal horn of the spinal cord.100 Opioid agonist activity

at peripheral receptors in the gut, on the other hand, inhibits the release of acetylcholine from the mesenteric plexus and stimulates µ receptors, thereby reducing muscle tone and peristaltic activity. The resulting delayed gastric emptying and gastric distention stimulate visceral mechanoreceptors and chemoreceptors, which trigger nausea and vomiting via a serotonergic signaling pathway. Alvimopan’s high polarity and large zwitterionic structure prevent penetration of the blood-brain barrier, such that potency at binding peripheral µ receptors is 200 times that of central µ receptors.98,101 By selectively targeting peripheral µ receptors, alvimopan prevents peripheral opioid emetogenic effects without affecting their central analgesic effects.102,103

CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

Cannabinoids Cannabinoids have demonstrated some success in the prevention of CINV but have never been shown to prevent PONV. KleineBrueggeney et al. administered 0.125 mg/kg IV tetrahydrocannabinol or placebo to 40 patients at high risk for PONV. The endpoints examined included PONV during the first 24 hours and side effects including sedation and psychotropic alterations. They found the tetrahydrocannabinol group had a 12% reduction in overall PONV compared with placebo. The authors postulated that this is a less significant effect than standard therapies, which produce a 25% reduction in PONV; this combined with an unacceptable side effect profile provoked the investigators to terminate the study before completion. Thus with the current evidence, cannabinoids cannot be recommended for prevention of PONV in high-risk patients.105

Risk-Based Prophylaxis Although all FDA-approved antiemetics have been proven to be safe in multiple clinical trials, no agent is without side effects. Therefore only patients at moderate to high risk for PONV should receive prophylaxis. A simplified risk score, such as the Apfel score (Fig. 34.13), can be useful for predicting PONV in adult patients undergoing inhalational anesthesia and thus for identifying which patients should be targeted for prophylaxis. The positive predictors included in the Apfel score are female gender, history of motion sickness or PONV, nonsmoking, and use of postoperative opioids.106 The incidence of PONV associated with 1, 2, 3, and 4 risk factors is 10%, 21%, 39%, 61%, and 79%, respectively (Fig. 34.14). An easy-to-remember guideline is that one antiemetic intervention is recommended for each risk factor present. It is also important to note that multimodal therapy should include drugs of different receptor classes, because repeat dosing of drugs of the same receptor class do not improve protection against PONV.107

Enhanced Recovery After Surgery A risk-based assessment of PONV and antiemetic prophylaxis should be part of an enhanced recovery pathway. Patients can be stratified based on established risk factor scoring systems. With increasing risk of PONV, multimodal prophylactic antiemetics should be implemented. Patients with 1 or 2 risk factors should be supplied with 2 prophylactic agents, whereas those with 3 or 4 risk factors should receive 3 prophylactic agents with consideration

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Because of its high binding affinity (Ki = 0.4 nM) and low dissociation rate (half-life = 30-44 min), alvimopan has low bioavailability (6%).104 Alvimopan is quickly absorbed, with a time to maximum plasma concentration of 2 hours after administration. Alvimopan also has a long half-life of 10 to 17 hours.104 Plasma clearance averages at 400 mL/min and is primarily mediated by biliary secretion. Alvimopan is metabolized by intestinal flora, with an active but clinically irrelevant amide hydrolysis metabolite (ADL 08-0011) that has lower binding affinity than alvimopan itself. Alvimopan is only available as a 12-mg oral capsule. Patients can be given 12 mg 30 minutes to 5 hours before surgery, followed by 12 mg twice a day for up to 7 days after surgery (maximum of 15 doses).104 Furthermore, 12-mg alvimopan has been shown to reduce OINV and to be well tolerated by ambulatory patients in the postdischarge period (Fig. 34.12C).103

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  Results of the IMPACT trial showing the effect of multimodal prophylactic antiemetic therapy on postoperative nausea and vomiting (PONV). N = 5161 patients. Blue dots show the average value for each number of prophylactic antiemetics. Orange dots show the incidence for each antiemetic or combination of antiemetics. Ond, Ondansetron; Dex, dexamethasone; Dro, droperidol. (From Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441–2451.)

of adding TIVA. In addition to prophylactic antiemetics, the choice of anesthetics, reduction in preoperative fasting, and adequate hydration may all contribute to the reduction of PONV in this patient population. An overall strategy of minimizing opioids in favor of regional anesthesia and adjuvant nonopioid medications also reduces the likelihood the patient will experience bowel dysfunction, nausea, and vomiting postoperatively.108

Multimodal Therapy No antiemetic agent can completely eliminate the incidence of PONV. A Cochrane review found the overall RR for antiemetics

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to be 0.60 to 0.80, that is, an RRR of 20% to 40%.22 However, the treatment effect might be slightly optimistic given that there is evidence of publication bias toward small studies with more positive results. The International Multicenter Protocol to quantify the relative impact of single and combined Antiemetics in a randomized Controlled Trial of factorial design (IMPACT) found that the RRs for 4 mg ondansetron, 4 mg dexamethasone, and 1.25 mg droperidol all equal approximately 0.75 (i.e., an RRR of 25% for each intervention; see Fig. 34.14).35 The study also demonstrated that each antiemetic intervention acted independently, which means that the efficacy of combination therapy can be estimated by multiplying the RR associated with each intervention. This independence of action implies that each additional antiemetic intervention is associated with less effectiveness than the previous one owing to an already decreased baseline risk of PONV. Using new classes of antiemetics synergy with mainstay drugs has reduced the incidence of PONV compared with conventional treatment. Numerous studies have demonstrated improved outcomes when multiple classes of antiemetics are used together as prophylaxis. One example is a study of chemotherapy-naive patients who were pretreated with antiemetic therapy comprising palonosetron (0.75 mg IV), dexamethasone (9.9 mg IV), and aprepitant (125 mg orally) The primary endpoint was the proportion of patients who did not experience vomiting and did not require rescue medication. Prevalence of the primary endpoint during the acute phase, delayed phase, and overall was 100%, 91.9%, and 91.9%.109 A prospective, double-blinded, randomized study compared aprepitant 40 mg orally with dexamethasone versus ondansetron 4 mg IV with dexamethasone in patients undergoing elective craniotomy. The aprepitant dexamethasone group significantly decreased POV up to 48 hours postoperatively (16% vs. 38%). There was no difference in the incidence of nausea or need for rescue medication between the study groups.110 A new combination drug available is NEPA, an oral fixed-dose combination of 300 mg netupitant and 0.5 mg palonosetron. In a study of 1455 chemotherapy patients who received dexamethasone plus either single-dose NEPA or palonosetron alone were evaluated for no emesis and no rescue therapy for 25 to 120 hours. Complete response was significantly higher in the NEPA versus the palonosetron group (76.9% vs. 69.5%, P = 0.001). The side effect profiles for both drugs were similar. This fixed-dose antiemetic combination offers improved prophylaxis from single-dose treatment.111 Acupuncture has been extensively studied as a nonpharmacologic method for the prevention of PONV. Although there are more than 300 acupuncture points, one point that has been shown to be efficacious is the P6 point (the sixth point along the pericardial meridian). It can be located at 2 inches proximal to the palmar aspect of the wrist, between the flexor carpi radialis and palmaris longus tendons. Stimulation of the P6 acupuncture point has shown efficacy for prevention and treatment of nausea and vomiting in the perioperative period. A Cochrane review summarizing 59 trials with 7667 participants drew the following conclusions. P6 acupoint stimulation significantly reduced postoperative nausea (RR = 0.60), vomiting (RR = 0.68), and the need for rescue antiemetics (RR = 0.64) compared with placebo or sham. There is no difference between P6 acupoint stimulation and established antiemetic pharmacotherapy for prevention of PONV. Lastly, there is insufficient evidence to suggest combination therapy is beneficial over acupressure or drug prophylaxis as a sole treatment.112 However, some studies have demonstrated mixed results. A study of 94 patients undergoing cesarean section with spinal

anesthesia were randomly assigned to receive transcutaneous accupoint electrical stimulation at the P6 point versus a sham location in hope of relieving both intraoperative and postoperative nausea and vomiting. No difference was found between the groups for either endpoint. The authors mentioned the study might have been underpowered.113 In general, direct acupuncture needle stimulation and electroacupuncture are associated with greater efficacy compared with acupressure. However, the optimal duration of stimulation and the amount of current is not known.

Emerging Developments Novel Antiemetic Drugs With the success of novel antiemetics like aprepitant and palonosetron, there is great promise for other new agents currently under investigation. These include newer NK1 receptor antagonists like the intravenous prodrug of aprepitant known as fosaprepitant, as well as the phase III–ready rolapitant (rolapitant hydrochloride, Schering-Plough SCH619734), both developed for CINV prevention. Upon injection, fosaprepitant is rapidly converted to aprepitant and therefore has the same mechanism of action as aprepitant. For CINV prevention, patients can receive fosaprepitant 150 mg as an IV infusion over 20 to 30 minutes before chemotherapy on the day of chemotherapy, followed by 2 to 3 days of treatment with other antiemetic agents like dexamethasone and ondansetron. Rolapitant appears to have several advantages over aprepitant, including a long half-life of 180 hours. It is more rapidly absorbed and does not inhibit CYP 2C9, 2C19, 2D6, and 3A4 or P-glycoprotein in vitro, suggesting that rolapitant has a low risk of interacting with concomitant medications.114 Oral doses of rolapitant appear to be rapidly absorbed and well tolerated without significant side effects. A dose-response study reported that rolapitant reduced POV up to 120 hours after surgery in high-risk patients, and that 70 mg and 200 mg were the most effective doses in terms of complete response.114 However, the optimal rolapitant dose has yet to be determined. In addition, rolapitant is currently available only in an oral formulation and therefore must be administered preoperatively. Amisulpride, a dopamine D2/D3 antagonist, is currently in phase III trials. It is being examined for its efficacy in the prevention of PONV in the adult surgical population. A multicenter study of adult inpatients undergoing elective surgery with general anesthesia randomly assigned participants to amisulpride 5 mg IV on induction or placebo. The primary endpoint was no retching or vomiting in the 24-hr postoperative period and no use of rescue antiemetics. The incidence of nausea was a secondary endpoint. In the U.S. component of the study, 46.9% of patients achieved the primary endpoint in the amisulpride group while 33.8% achieved in the placebo group (P = 0.026). Nausea occurred less in the study group. There was no clinically significant difference in the safety profile of the study drug compared with the placebo. Specific concerns examined were QT prolongation, extrapyramidal side effects, and sedation that were problematic for this group of antiemetics in the past.115

Postdischarge Nausea and Vomiting As the number of surgeries performed on an outpatient basis continues to grow, there is increasing interest in using antiemetic agents to prevent and treat postdischarge nausea and vomiting



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(PDNV). Because outpatient procedures are typically less invasive and shorter in duration than inpatient procedures, the relatively lower exposure to emetogenic inhalational anesthetics and opioids predicts a relatively lower incidence of PONV in the postanesthesia care unit. However, a study in 2170 ambulatory patients in the United States found that the incidence of nausea and vomiting after discharge from the hospital was 37%, even after intraoperative prophylaxis with ondansetron or dexamethasone.116 PDNV is

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particularly a concern because it occurs when patients no longer have access to fast-acting intravenous rescue treatment, and PDNV limits their ability to tolerate oral antiemetics. Ideal antiemetics for PDNV should have a long duration of action with a safe side effect profile, such as dexamethasone, palonosetron, TDS, and aprepitant. However, further studies are required to investigate the absolute and relative value of these and other antiemetics in the postdischarge setting.

Key Points • Despite new insights into relevant target receptor function and the successful development of novel antiemetic agents, the actual mechanisms of PONV remain unknown. • Ondansetron is the most commonly used serotonin type 3 (5-HT3)-receptor antagonist for prevention and treatment of PONV and CINV, probably because it is not associated with sedation that might slow recovery from anesthesia. • Low-dose droperidol (0.625–1.25 mg), a dopamine type 2 (D2) receptor antagonist, used to be the most commonly used antiemetic for the prevention of PONV; however, potential for torsades de pointes and cardiac arrest led to an FDA black box warning that has significantly reduced its usage in the United States. • Metoclopramide is an alternative D2 receptor blocker; 25 mg is the minimally effective dose for preventing PONV. Extrapyramidal symptoms associated with the 25-mg dose affect less than 1% of patients, but like other D2 antagonists, arrhythmias have been described. • The antiemetic effect of glucocorticoids such as dexamethasone is well established although poorly understood. Most doseresponse studies suggest that 4 mg is the minimally effective dose with equal efficacy as 4 mg ondansetron and 1.25 mg droperidol.

• Aprepitant is the first FDA-approved NK1 receptor antagonist. An oral dose of 40 mg aprepitant reduces nausea by about 30% and vomiting by more than 50%. It is thus particularly useful for surgeries in which postoperative vomiting might affect the success of the surgery. • TDS is the only approved anticholinergic for prevention of PONV. RRR is comparable to other antiemetics; its long duration of action makes TDS a suitable antiemetic for preventing PDNV in ambulatory patients. • H1 antagonists such as dimenhydrinate, cyclizine, and promethazine are less popular, mainly because of their sedative and psychotropic side effects and the potential for vein irritation and tissue damage. • Alvimopan is a peripheral opioid receptor antagonist indicated for the prevention of ileus after colectomies. Secondary data analyses suggest that it might reduce OINV. • The effectiveness of antiemetics when given prophylactically is critically dependent on the patient’s risk for PONV. This can be easily assessed using a simplified risk score for PONV consisting of four risk factors: female sex, history of motion sickness and/or PONV, nonsmoking status, and anticipated use of postoperative opioids.

Key References

Carlisle J, Stevenson C. Drugs for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2006;(3):CD004125, A systematic review of more than 730 trials that assessed the efficacy of all antiemetic agents as well as their associated side effects. The individual relative risk versus placebo for all effective antiemetics ranged between 0.60 and 0.80. (Ref. 22). Cubeddu LX, Hoffmann IS, Fuenmayor NT, et al. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med. 1990;322:810–816. One of the first papers to show that ondansetron safely and effectively reduced the incidence of CINV in cancer patients undergoing chemotherapy. The results also suggested that cisplatin treatment triggered enterochromaffin cells to release serotonin and that ondansetron worked by blocking 5-HT3 receptors. (Ref. 2). Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014;118:85–113. Hvarfner A, Hammas B, Thörn SE, et al. The influence of propofol on vomiting induced by apomorphine. Anesth Anal. 1995;80:967–969. This study reported that propofol did not protect against nausea and vomiting at nonsedative doses, but that at sedative doses, propofol did have an antiemetic effect similar to that of midazolam. Therefore the antiemetic effect often attributed to propofol is more likely an effect of sedation. (Ref. 76). Kovac AL, O’Connor TA, Pearman MH, et al. Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial. J Clin Anesth. 1999;11:453–459. Patients who received 4 mg IV

Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441–2451. A large multicenter trial of more than 5000 patients demonstrating that the relative risk reduction for three commonly used antiemetic interventions are all in the range of 25%, that efficacy is independent of patient risk, and that antiemetic drugs of different classes act independently of each other. (Ref. 35). Apfel CC, Laara E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from crossvalidations between two centers. Anesthesiology. 1999;91:693–700. According to the simplified PONV risk score reported in this study, patients are likely to benefit from receiving antiemetic prophylaxis if they have at least two of the following four risk factors: female gender, history of PONV and/or motion sickness, nonsmoking status, and use of postoperative opioids. (Ref. 106). Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005;102:543–549. The CYP2D6 gene is responsible for metabolism of several antiemetic drugs, including ondansetron. Patients with three functional copies of the CYP2D6 gene were more likely to require rescue treatment for vomiting after prophylaxis with ondansetron. Some interindividual differences in response to prophylaxis might therefore be due to genetic variations among patients. (Ref. 12).

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ondansetron for prophylaxis against PONV did not benefit from additional doses of ondansetron in the postanesthesia care unit. This study highlights the importance of administering antiemetics of different receptor classes for prophylaxis and/or rescue treatment to increase protection against PONV. (Ref. 107). Rojas C, Stathis M, Thomas AG, et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg. 2008;107:469–478. The first molecular-level study to differentiate between palonosetron and first generation 5-HT3-receptor antagonists. Only palonosetron binds allosterically and cooperatively to the 5-HT3 receptor, and its effect on receptor function persists longer than its binding to the receptor at the cell surface, suggesting that palonosetron induces receptor internalization. These unique mechanisms might account for palonosetron’s superior efficacy against delayed PONV. (Ref. 16). Wallenborn J, Gelbrich G, Bulst D, et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ. 2006;333:324. A dose-response trial in 3140 patients that determined that 25 mg was the minimum effective dose of metoclopramide for PONV prophylaxis, and that the commonly used dose of 10 mg was insufficient. Extrapyramidal symptoms associated with the 25-mg dose affected less than 1% of patients. (Ref. 31).

References 1. Raeder J. History of postoperative nausea and vomiting. Int Anesth Clin. 2003;41:1–12. 2. Cubeddu LX, Hoffmann IS, Fuenmayor NT, et al. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatininduced nausea and vomiting. N Engl J Med. 1990;322:810–816. 3. Apfel CC, Korttila K, Abdalla M, et al. An international multicenter protocol to assess the single and combined benefits of antiemetic interventions in a controlled clinical trial of a 2x2x2x2x2x2 factorial design (IMPACT). Control Clin Trials. 2003;24:736–751. 4. Jokela RM, Cakmakkaya OS, Danzeisen O, et al. Ondansetron has similar clinical efficacy against both nausea and vomiting. Anaesthesia. 2009;64:147–151. 5. Tang J, Wang B, White PF, et al. The effect of timing of ondansetron administration on its efficacy, cost-effectiveness, and cost-benefit as a prophylactic antiemetic in the ambulatory setting. Anesth Analg. 1998;86:274–282. 6. Tramer MR, Reynolds DJ, Moore RA, et al. Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials. Anesthesiology. 1997;87:1277–1289. 7. Benedict CR, Arbogast R, Martin L, et al. Single-blind study of the effects of intravenous dolasetron mesylate versus ondansetron on electrocardiographic parameters in normal volunteers. J Cardiovasc Pharmacol. 1996;28:53–59. 8. Charbit B, Albaladejo P, Funck-Brentano C, et al. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology. 2005;102:1094–1100. 9. Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol. 2002;20:2805–2811. 10. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs. 1998;55:173–189. 11. Hickok JT, Roscoe JA, Morrow GR, et al. Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology Program Study of 360 cancer patients treated in the community. Cancer. 2003;97:2880–2886. 12. Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do

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CHAPTER 34  Pharmacology of Postoperative Nausea and Vomiting

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